rs137854613

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001099404.2(SCN5A):c.4867C>T(p.Arg1623Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN5A
NM_001099404.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38551505-G-A is Pathogenic according to our data. Variant chr3-38551505-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551505-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4867C>T	p.Arg1623Ter	stop_gained	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.4864C>T	p.Arg1622Ter	stop_gained	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4867C>T	p.Arg1623Ter	stop_gained	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4864C>T	p.Arg1622Ter	stop_gained	28/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152030

Hom.:

Cov.:

FAILED QC

Gnomad AFR

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0.00

Gnomad AMI

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0.00

Gnomad AMR

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0.00

Gnomad ASJ

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0.00

Gnomad EAS

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0.00

Gnomad SAS

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0.00

Gnomad FIN

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0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

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0.00

Gnomad4 ASJ exome

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0.00

Gnomad4 EAS exome

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0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74272

Gnomad4 AFR

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0.00

Gnomad4 AMR

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0.00

Gnomad4 ASJ

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0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

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0.00

Gnomad4 FIN

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0.00

Gnomad4 NFE

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0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 394 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate that R1623X results in no inward sodium current, indicating this variant causes a non-functional sodium channel (PMID: 16325048); This variant is associated with the following publications: (PMID: 19027780, 18436145, 17368591, 30147658, 20539757, 20129283, 28341781, 28552050, 15840483, 26187847, 30203441, 14523039, 31043699, 33221895, 31402444, 32600061, 33087929, 33131149, 28069705, 29574140, 16325048) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg1623) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with bradychardia or Brugada syndrome (PMID: 14523039, 16325048, 29574140). ClinVar contains an entry for this variant (Variation ID: 9374). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 14523039, 16325048, 20539757). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg1629) have been determined to be pathogenic (PMID: 18361072, 20129283, 25829473). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 12, 2017	The p.Arg1623X variant in SCN5A has been reported in 2 heterozygous individuals with Brugada syndrome (Todd 2005, Mikayama 2005), 1 compound heterozygous individual with sick sinus syndrome (Benson 2003), and one heterozygous individual with ARVC who also carried a heterozygous pathogenic splice variant in PKP2 (te Riele 2017). The p.Arg1623X variant segregated with Brugada syndrome in one family member and with heart block in 3 family members (Benson 2003, Todd 2005). This variant was also absent from large population studies. This variant has also been reported in ClinVar (Variation ID 9374). This nonsense variant leads to a premature termination codon at position 1623. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While the effect on the protein is unknown, in vitro functional studies provide some evidence that the p.Arg1623X variant causes a loss of function (Benson 2003, Makiyama 2005, Gui 2010). Heterozygous loss of function variants of the SCN5A gene have been previously reported for DCM (Olson 2005), Brugada syndrome (Kapplinger 2010), ventricular fibrillation (Chen 1998), and atrioventricular block and cardiac conduction defects (Baruteau 2012). In summary, this variant meets criteria to be classified as pathogenic for SCN5A-related disorders in an autosomal dominant manner based upon segregation studies, absence from controls, functional evidence, and impact to the protein. -

Cardiac arrhythmia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2023	This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2024	Variant summary: SCN5A c.4867C>T (p.Arg1623X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.1e-06 in 1461728 control chromosomes (gnomAD v4.1). c.4867C>T has been reported in the literature in multiple individuals affected with cardiac phenotypes including sick sinus syndrome, first-degree heart block, or Brugada syndrome (e.g. Benseon_2003, Ciconte_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 14523039, 33221895). ClinVar contains an entry for this variant (Variation ID: 9374). Based on the evidence outlined above, the variant was classified as pathogenic. -

SCN5A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 15, 2022

The SCN5A c.4867C>T (p.Arg1623Ter) variant, also referred to as c.4864C>T (p.Arg1622Ter), is a nonsense variant that results in the substitution of arginine at amino acid position 1623 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. The c.4867C>T variant has been reported in a heterozygous state in at least five individuals, including four with Brugada syndrome (BrS) and one individual with left ventricular noncompaction, ventricular tachycardia, and prolonged QT (PMID: 16325048; PMID: 15840483; PMID: 32600061; PMID: 33221895). One of the individuals with BrS was also noted to have a brother who carried the variant and presented with features suggestive of BrS (PMID: 15840483). Two additional individuals have been reported with either confirmed or possible BrS (PMID: 20129283) and the variant has also been reported in a compound heterozygous state in an individual with sick sinus syndrome (PMID: 14523039). Three family members of the individual with sick sinus syndrome who carried the variant were not identified as affected, but were noted to have first-degree heart block (PMID: 14523039). The c.4867C>T variant was not detected in 1410 control individuals (PMID: 14523039; PMID: 20129283) and at least 150 additional control chromosomes. This variant failed filters in the Genome Aggregation Database version 2.1.1 and version 3.1.2; therefore, this information cannot be reliably used. Three patch clamp studies in HEK293 cells overexpressing the c.4867C>T variant demonstrated no Na+ current detection compared to wild type (PMID: 14523039; PMID: 16325048; PMID: 20539757). Similar results of no Na+ current detection were obtained when Xenopus oocytes were injected with variant cRNA when compared to wild type. A cell surface biotinylation experiment using HEK293 cells transfected with the c.4867C>T variant showed very small fractions at the plasma membrane suggesting trafficking deficiency (PMID: 20539757). Based on the available evidence, the c.4867C>T (p.Arg1623Ter) variant is classified as pathogenic for SCN5A-related disorders. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 17, 2021

- -

Sick sinus syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Long QT syndrome 3

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Oct 31, 2014

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2022

The p.R1623* pathogenic mutation (also known as c.4867C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4867. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration was first reported in a pediatric patient with sick sinus syndrome who also carried a second missense alteration in SCN5A. The p.R1623* mutation was also seen in the patient's mother, maternal aunt and maternal grandmother who were all found to have heart block (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28). This alteration has also been reported in subjects with clinical Brugada syndrome (Todd SJ et al. Heart Rhythm, 2005 May;2:540-3; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6) and has been seen in a subject with arrhythmogenic right ventricular cardiomyopathy (ARVC) who also harbored a splicing alteration in PKP2 (Te Riele AS et al. Cardiovasc. Res., 2017 Jan;113:102-111). Functional studies support that this alteration results in a non-functional sodium channel (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6; Gui J et al. PLoS ONE, 2010 Jun;5:e10985). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Familial isolated arrhythmogenic right ventricular dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

Vest4

0.96

GERP RS

3.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over